Making Old Hearts Young

MOLLY ZHAO

The expression, “you can’t mend a broken heart,” is used to emphasize the intense sadness that often accompanies the end of a romantic relationship. For many Americans, the phrase is all too true medically. Heart disease is the leading cause of death in the United States.1 It kills 600,000 people in this country every year, and coronary heart disease alone costs the US a staggering $108.9 billion annually.1

One particularly debilitating manifestation of heart disease is heart failure, which was a contributing cause in 1 out of 9 American deaths in 2009.2 “While heart failure can result from damage to heart muscle cells, most commonly due to damage from blocked heart arteries, almost 50% of cases of heart failure occur in hearts that still pump well,” Dr. Robert Glueck (A.B. Harvard College ‘73, M.D. Harvard Medical School ’77, Fellow, American College of Cardiology) said. “But [these hearts] become stiff and inelastic and cause fluid to back up into the lungs.” Various aging-related changes in the human heart can conspire to result in this kind of heart failure. New research from Professor Richard Lee at the Harvard Stem Cell Institute suggests that some features of cardiac aging may be reversible.

In collaboration with Professor Amy Wagers, also from the Stem Cell Institute, Lee has been working on aging and its effect on the heart in mice. Hypertrophy, or thickening of heart muscle cells, is a prominent characteristic of the aging mouse heart, as well as of the aging hearts of other species, including humans. To uncover the molecular differences between a hypertrophic heart and a non-hypertrophic young heart, Lee and Wagers used heterochronic parabiosis, a process in which the bodies of the two mice are surgically connected along their sides so that they form one large cardiovascular circuit. The researchers performed the procedure on mice of different ages, one old and one young, to expose them to each other’s circulatory systems for four weeks. The merging of the two circulatory systems exposes each mouse to the blood, hormones and molecular factors that are circulating in the other mouse’s circulatory system. After four weeks of exposure, cardiac hypertrophy was reduced in the older heart, and the size of cardiomyocytes (heart muscle cells) also declined to match the size of young cells. The researchers hypothesized that certain molecules in the younger heart circulatory system must have come in contact with that of the older heart and led to the reduction of hypertrophic changes.

GDF11 seems to counter the hypertrophy of aging, because treatment of old mice that had cardiac hypertrophy with GDF11 reduced their cardiac hypertrophy.”

Lee said, “We looked at lipids; we looked at metabolites. Then we set up a collaboration with a biotechnology company in Colorado called SomaLogic that had an interesting technology for analyzing factors in blood. And by working closely with SomaLogic, we found the likely factor.” After several more rounds of experiments, they identified the circulatory factor as a member of the superfamily TGF-β called Growth Differentiation Factor-11 (GDF11). GDF11 is a gene that encodes a protein that is a member of a family of TGF-βproteins. This protein family regulates cell growth in embryonic and adult tissues. GDF11 seems to counter the hypertrophy of aging, because treatment of old mice that had cardiac hypertrophy with GDF11 reduced their cardiac hypertrophy.

This research has a long way to go before it could be clinically applicable in humans, so we may not be fixing broken hearts any time soon. But perhaps one day, Lee’s study will help doctors make an old heart young once again.